title: The extracellular domain of Notch2 increases its cell-surface abundance and ligand responsiveness during kidney development.
abstract: Notch2, but not Notch1, plays indispensable roles in kidney organogenesis, and Notch2 haploinsufficiency is associated with Alagille syndrome. We proposed that proximal nephron fates are regulated by a threshold that requires nearly all available free Notch intracellular domains (NICDs) but could not identify the mechanism that explains why Notch2 (N2) is more important than Notch1 (N1). By generating mice that swap their ICDs, we establish that the overall protein concentration, expression domain, or ICD amino acid composition does not account for the differential requirement of these receptors. Instead, we find that the N2 extracellular domain (NECD) increases Notch protein localization to the cell surface during kidney development and is cleaved more efficiently upon ligand binding. This context-specific asymmetry in NICD release efficiency is further enhanced by Fringe. Our results indicate that an elevated N1 surface level could compensate for the loss of N2 signal in specific cell contexts.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Liu
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.forename: Scott
authors.initials: S
authors.lastname: Boyle
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Andrew
authors.initials: A
authors.lastname: Zhang
authors.forename: David R
authors.initials: DR
authors.lastname: Piwnica-Worms
authors.forename: Ma Xenia G
authors.initials: MX
authors.lastname: Ilagan
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D050506:Mutant Chimeric Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009399:Nephrons / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D050199:Podocytes / Q000166:cytology / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D050506:Mutant Chimeric Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2